A revolution in technology has moved genetic studies forward at a remarkable pace over the last 5 years, and clear genetic contributions to smoking behavior have been identified. Our group was the first to report the association of nicotine dependence with the chromosome 15q25.1 region, which includes the CHRNA5-CHRNA3-CHRNB4 cholinergic nicotine receptor subunit genes. The strongest genetic association findings for nicotine dependence, lung cancer and chronic obstructive pulmonary disease then converged to implicate this region. Our studies and several meta-analyses have convincingly shown that SNPs in the CHRNA6-CHRNB3 receptor subunits and nicotine metabolizing gene CYP2A6 are also associated with heavy smoking and nicotine dependence. The goal of this project is to further identify and characterize genetic findings for nicotine dependence and to integrate how these associations contribute to successful smoking cessation. Specific Aim 1 is to catalogue, characterize, and test identified variants and fine map nicotinic receptor genes and nicotine metabolizing genes. This aim will build upon custom targeted sequencing from the Center for Inherited Disease Research (CIDR) to catalogue variation in the nicotinic receptors and nicotine metabolizing genes in almost 3,000 nicotine dependent or non-dependent subjects. Specific Aim 2 is to evaluate genetic associations for nicotine dependence in large-scale studies, including our own replication sample and through participation in meta-analyses and consortia. Specific Aim 3 is to evaluate genetic associations for smoking cessation in large-scale studies. We will actively generate and participate in meta-analyses and consortia assessing smoking cessation related phenotypes, and we will also build upon our collaboration with Dr. Timothy Baker, who has data from smoking cessation trials along with phenotypic and genetic data from the Pfizer clinical trial of varenicline (Chantix(R)). This project will continueto accelerate the discovery of variation in molecular pathways that govern the development of nicotine dependence and extend our work toward the understanding of smoking cessation. By capitalizing on the resources and collaborations we have previously developed, this study will take an important next step along the cutting edge of genomic science and move the field to the next level of understanding the genetics of nicotine dependence and smoking cessation.